1. Field of the Invention
This invention relates to novel key intermediates, 3-hydoxy-2-halocycloheptenones and 3-alkoxy-2-halocycloheptenones, which are useful for the synthesis of drug medicine. In detail, this invention relates to preparation of the key intermediates of novel cycloheptimidazole derivatives that have angiotensin II receptor antagonistic activities and are therefore useful for the treatment of hypertension, congestive heart failure and so on.
2. Description of the Prior Art
Many compounds containing cyclohept rings possess potent physiological activities. For example, we proposed cycloheptimidazoles of general formula (6) that have angiotensin II receptor antagonistic activities and are therefore useful for the treatment of hypertension or congestive heart failure. (Japanese Patent laid-open Publication 5-320139, 7-149761 and 8-73454.) ##STR2##
(wherein: R.sub.5 is hydrogen atom or lower alkyl group, R.sub.6 is carboxyl group, tetrazolyl group) However, the synthetic method of the cycloheptaimidazoles, shown in general formula (6), is unfavorable on an industrial scale because of the following reasons.
1) The starting material, tropolone is expensive. PA1 2) A large number of process steps are needed. PA1 3) This procedure is not applicable to a wide range of cycloheptanoid compounds.
Judging from the application of known method, it is a common concept that 1,3-cycloheptadione (8), prepared from the compound (2), is halogenated at the 2 position of compound (8) to obtain the general formula (1) containing compound (3) and (4). ##STR3##
(wherein: R.sub.2 and R.sub.3 is lower alkyl group, X is bromine atom or chlorine atom.)
In other words Cyclohepta-1,3-dione (8) can be obtained by known method. First, cyclopropanation of compound (2) in the presence of Et.sub.2 Zn and CH.sub.2 I.sub.2 (Simmons-Smith reaction) gives the bicyclic compound (7) (L. Hadjiarapoglou, Synthesis, 525, 1996). Second, ring enlargement of (7) using FeCl.sub.3 or periodic acid gives the compound (8) (T. Saegusa, Organic Synthesis 59, 113; M. C. Pirrung, J. Org. Chem. 52, 3606, 1987). Then the halo analogue (3) seems to be prepared in a similar manner as described by R. G. Shepherd (J. Chem. Soc. Perkin Trans. I, 2153,1987), and its etherification affords 2-halo-3-alkoxycyclohept-2-enone(4).
However, Simmons-Smith reaction is not useful industrially because of following reasons.
1) The reaction condition is anhydrous. 2) Et.sub.2 Zn is subject to autoignition.
Moreover, the objective compound (3) is not obtained under several conditions for halogenation of the compound (8), and dihalogenation reaction occurs and 2,2-dihalo-1,3-cycloheptandione (9) is obtained as a main product.
Similarly, well-known procedure was not applicable to the synthesis of the compounds (3) and (4). Furthermore, although the compounds (10) (Chem. Abstr. 77, 48038k, 1972 (U.S. Pat. No. 3,658,841)), (11) and (12) (Chem. Abstr. 89, 179583e, 1978 (J. Org. Chem. 43, 4241, 1978)) have already been known, 3-hydroxy-2-halocycloheptenone and 3-alkoxy-2-halocycloheptenone, which are shown as general formula (1), below, are not yet reported and are new compounds. ##STR4##